PROJECT SUMMARY Traumatic brain injury (TBI) is a devastating medical condition that affects more than 1.7 million civilians in the US and represents an unmet clinical need. Effective therapies are urgently needed, as TBI is associated with high rates of hospitalization, mortality, and disability. Previous clinical trials have failed to demonstrate thera- peutic efficacy in patients with TBI. This project focuses on evaluating the therapeutic efficacy of a novel multifunctional biologic?recombinant human proteoglycan 4 (rhPRG4), also known as lubricin?in TBI. rhPRG4 effectively interacts with both hydrophilic and hydrophobic surfaces, and has strong anti-adhesive and anti-inflammatory properties. When administered peripherally in a rat model of TBI, rhPRG4 crosses the blood-brain barrier (BBB) in the injured brain parenchyma, but is absent from the uninjured parts of the brain. Our preliminary data show that rhPRG4 dramatically decreases the post-traumatic production of proinflammatory mediators and matrix metallo- proteinases, and reduces the influx of inflammatory cells into the injured brain parenchyma. rhPRG4 also has a unique ability to stabilize the BBB, whose function is affected by TBI. These observations suggest that the rhPRG4 biologic could limit the destruction of neural tissue observed in TBI and, consequently, improve neurological outcome after injury. There are two major goals of this study: (1) to assess the efficacy of rhPRG4 in engaging with its putative targets and enhance our understanding of rhPRG4's ability to stabilize the BBB in acute phase of injury, and (2) to obtain preclinical data on long-term efficacy of rhPRG4 in reducing the neuronal loss and improving functional outcome after TBI.